PROJECT SUMMARY Current approaches to treat sensorineural hearing loss (SNHL) in newborns suffering from congenital cytomegalovirus (CMV) infection rely on off-label, systemic antiviral therapy requiring high dose, long duration treatment with demonstrated hematologic toxicity, carcinogenicity, and teratogenicity. Furthermore, it is unknown whether systemic delivery of antivirals maintain inner ear drug concentrations within an appropriate therapeutic window for sufficient lengths of time to achieve therapeutic effect. A novel delivery system for long- term, controlled release of antivirals to the inner ear would constitute a dramatic improvement in CMV-related SNHL treatment options. Our proposed strategy uses Unisun technology to create a long-acting single transtympanic injection of ganciclovir-loaded microspheres for round window membrane (RWM) localization and sustained-release to the inner ear. The central advantage of our approach is that Unisun allows for precise control of particle size, shape, material, and drug release rates. Our long-term goal is for transtympanic delivery of Unisun-enabled ganciclovir-loaded microspheres to be the standard-of-care for newborns suffering from CMV-related SNHL. We hypothesize that microspheres can be retained on the RWM for over four weeks and that ganciclovir release can be maintained (~65 g/day) to sustain a therapeutic concentration in the inner ear fluid. We expect that this novel approach to localize ganciclovir treatment to the inner ear will dramatically improve the safety and efficacy of antiviral therapy for CMV-related SNHL over current non-FDA approved options. Orbis? research team will first develop and characterize the relationship between the microsphere size, material, drug concentration and ganciclovir release profiles to establish the feasibility of achieving long-term, controlled release to the inner ear (Aim 1). We will then determine the optimal microsphere immobilization strategy to enable RWM localization for a minimum of one-month with minimal toxicity in a guinea pig model (Aim 2). This Unisun-enabled drug-delivery strategy addresses issues of dosage accuracy and long-term release. In addition, Unisun-based encapsulation is highly adaptable and can serve as a transtympanic delivery platform for multiple drug classes. This unique strategy has significant potential to become the standard-of-care for treatment of CMV-related SNHL.